HMAs Promote Megakaryocyte Maturation in TET2-Mutated MDS With Thrombocytopenia

Treatment with hypomethylating agents (HMAs) was associated with significant platelet response and megakaryocyte maturation in both patients with myelodysplastic syndromes (MDS) with severe thrombocytopenia and TET2 mutations, as well as a corresponding TET2 knockout mouse model, according to Yue Wei, PhD.

Prior research has established that platelet response or recovery in HMA therapy is associated with favorable outcomes in patients with MDS. For instance, results from a 2019 systematic hematopathological analysis demonstrated that patients with higher-risk MDS who achieved platelet response after 1 cycle of treatment with the HMA decitabine had a longer overall survival compared with those who did not have early platelet response.¹ Additionally, decitabine was shown to induce dysplastic megakaryocyte maturation in the bone marrow of patients with early platelet response.

Based on this rationale, findings from a longitudinal analysis presented at the 2025 ASH Annual Meeting showed that significant platelet count recovery occurred at approximately days 65 to 70 of HMA therapy in patients with MDS treated with single-agent HMA therapy (n = 390).² Notably, this platelet response was only observed in patients with TET2 mutations and severe thrombocytopenia, defined as a baseline platelet count of less than 33 x 10⁹/L. Follow-up research in a TET2 knockout mouse model confirmed these findings.

Additionally, treatment with azacitidine did not promote early megakaryocyte differentiation in the bone marrow of the TET2 knockout mouse model but did promote megakaryocyte polyploidization. Furthermore, the investigators found that HMAs activate signals that are crucial for megakaryocyte maturation in the bone marrow.

“It is exciting to study megakaryopoiesis in MDS,” Wei said in an interview with OncLive®. “[This is] a relatively weak field, but I’m happy we started this project, and we got important findings. The biology part is exciting, and I’m happy that there might be translational potential for patients with MDS.”

In the interview, Wei discussed research gaps in thrombocytopenia management strategies that exist for patients with MDS, findings from this study that highlighted the role of HMAs in platelet response, the potential clinical relevance of using a mouse model to investigate this treatment approach, and future work that is planned to validate these findings in patient cohorts.

Wei is an assistant professor in the Department of Leukemia in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

OncLive: What are some of the most pressing unmet needs that exist for patients with thrombocytopenia?

Wei: Thrombocytopenia is one of the most important clinical issues for patients with MDS, together with [effects] like anemia and low white blood cell counts. Especially for thrombocytopenia, there are not many options for treatment. Even research to study thrombocytopenia in MDS is relatively behind compared with [research in] other issues in MDS. [Thrombocytopenia is] maybe one of the weakest links in MDS that we need to study.

What were the rationale and design of the study of platelet responses with HMAs in MDS that was presented at ASH 2025?

From the translational perspective, we first examined thrombocytopenia in the context of hypomethylation treatment. Hypomethylation is the most important [class of] drugs for patients with MDS, and hematologists observe an important phenomenon called the platelet response that is related to the improvement of thrombocytopenia in HMA treatment and associated with good prognosis in patients. The study of platelet response has multiple values regarding the mechanisms of the disease, the therapy for the disease, and even the improvement of HMA treatment. We studied that by evaluating a patient cohort and found that [platelet response] perhaps involves the TET2 mutation, one of the most important mutations in patients with MDS.

Because of the complication of studying thrombocytopenia directly using patient samples, we decided to use a mouse model with TET2 knockout to mimic this disease. This is a well-known model for MDS. We decided to study the relationship between HMA treatment, thrombocytopenia, and platelet improvement using this model. It worked well, and we made important findings about the biology and related to HMA therapy for patients.

What findings with HMAs were seen in the cohort of patients with MDS?

The cohort of patients told us the most important finding: the potential involvement of TET2 compared with other common mutations in this disease. This has not been published before. We need to verify the results, but they give us important hints about the clinical value of this mutation and led us to use established mouse models to study the important platelet and thrombopenia phenomenon in this disease. With an available animal model, we can study the biology [of the disease], apply HMAs, and maybe eventually, if we find biomarkers or candidates for potential therapeutic approaches, we can use this model to test the idea first. [The study of the patient cohort led to] important findings to let us study the mechanism [of the disease and gave] us a good model to use.

What additional findings were observed with HMAs in the MDS mouse model?

We used the mouse model because we had the idea that HMAs improve platelet counts in early treatment cycles and have prognostic value, but we had no idea what the HMAs regulate during this process. Do they affect the early stem cells for the megakaryocytes and platelets? Or do they affect the maturation of the megakaryocytes at a later stage and improve platelet production? We had no biological ideas for this event. Using this mouse model, we determined that the main effect of HMAs in platelet response is through promoting late-stage megakaryocyte maturation and platelet production. That’s one of the most important findings that can help us pinpoint the major biological event that HMA is affecting during this platelet response.

What additional next steps might contribute to the further understanding of the role of HMAs on megakaryocyte maturation in patients with MDS?

[We can now] perform single-cell sequencing analyses and identify important biomarkers or even future therapeutic targets that can be combined with HMAs to intervene and probably further improve platelet production in patients with MDS. With these findings, including the process of megakaryocyte maturation affected by HMAs and the marker genes we found, we can use this [model] candidate to translate into patient analysis. Now we are working on analyzing megakaryocytes from patients with MDS treated with HMAs [who have achieved] this important platelet response to see whether we can confirm the results [from this study] and [find] the candidate genes identified in animal [models] in patient cohorts. If that happens, these will be important findings to explain the biology of the platelet response in HMA treatment in patients. That will further give us the confidence to generate translational approaches to target this event in patients.

We hope we can answer [questions about] HMA treatment improvement for the megakaryocyte and platelet production fields for patients. We are determined to continue working on this study and maybe apply large grants to support further expansion of the study. I hope soon we can report findings in patients as a validation of our animal model results so we can move on.

Disclosures: Wei had no financial relationships to disclose.

References

1. Stomper J, May AM, Joeckel TE, Bronsert P, Werner M, Lübbert M. Decitabine-induced early platelet response, a predictor of favorable outcome during hypomethylating treatment of MDS, is associated with In Vivo megakaryocytic differentiation. Blood. 2019;134(suppl 1):4265. doi:10.1182/blood-2019-128141
2. Wei Y, Lyu Y, Sasaki K, et al. Hypomethylation agent improves late-stage megakaryocyte maturation in MDS. Blood. 2025;146(suppl 1):196. Doi:10.1182/blood-2025-196